We have measured regional cerebral blood flow (rCBF) with oxygen-15 and positron emission tomography (PET) in patients with schizophrenia and other neuropsychiatric disorders during performance of a battery of neuropsychological tasks putatively involving working memory and abstract reasoning as well as during performance of matched sensorimotor control tests. In monozygotic twins discordant for schizophrenia, an area of the left inferior frontal gyrus corresponding to Brodmann's Areas 9 and 46 of the dorsolateral prefrontal cortex was lower in affected compared with unaffected twins during a frontal lobe-specific task in which this area is consistently activated in normal subjects. The left hippocampus and superior temporal gyrus, discriminated between affected and unaffected co-twins in each and every pair and was more active in each of the ill twins. One of the most intriguing findings in this study is a tendency for the intercotwin differences in left inferior frontal and left hippocampal activity during the WCS to be negatively correlated. This result suggests that abnormal limbic- prefrontal circuitry may underly the cognitive deficits common in schizophrenia. During a more traditional working memory test, Delayed Response Alternation, patients were markedly hyporesponsive int he prefrontal cortex, even when compared to normal controls with identical performance levels. The effects of pharmacological interventions are also being explored.